Diabetes and high-glucose could upregulate the expression of receptor for activated C kinase 1 in retina

Jian Tan; Ang Xiao; Lin Yang; Yu-Lin Tao; Yi Shao; Qiong Zhou

doi:10.4239/wjd.v15.i3.519

Diabetes and high-glucose could upregulate the expression of receptor for activated C kinase 1 in retina

World J Diabetes. 2024 Mar 15;15(3):519-529. doi: 10.4239/wjd.v15.i3.519.

Authors

Jian Tan¹, Ang Xiao¹, Lin Yang¹, Yu-Lin Tao¹, Yi Shao¹, Qiong Zhou²

Affiliations

¹ Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China.
² Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China. zqndyfy@163.com.

Abstract

Background: Diabetic retinopathy (DR) is a major ocular complication of diabetes mellitus, leading to visual impairment. Retinal pigment epithelium (RPE) injury is a key component of the outer blood retinal barrier, and its damage is an important indicator of DR. Receptor for activated C kinase 1 (RACK1) activates protein kinase C-ε (PKC-ε) to promote the generation of reactive oxygen species (ROS) in RPE cells, leading to apoptosis. Therefore, we hypothesize that the activation of RACK1 under hypoxic/high-glucose conditions may promote RPE cell apoptosis by modulating PKC-ε/ROS, thereby disrupting the barrier effect of the outer blood retinal barrier and contributing to the progression of DR.

Aim: To investigate the role and associated underlying mechanisms of RACK1 in the development of early DR.

Methods: In this study, Sprague-Dawley rats and adult RPE cell line-19 (ARPE-19) cells were used as in vivo and in vitro models, respectively, to explore the role of RACK1 in mediating PKC-ε in early DR. Furthermore, the impact of RACK1 on apoptosis and barrier function of RPE cells was also investigated in the former model.

Results: Streptozotocin-induced diabetic rats showed increased apoptosis and up-regulated expression of RACK1 and PKC-ε proteins in RPE cells following a prolonged modeling. Similarly, ARPE-19 cells exposed to high glucose and hypoxia displayed elevated mRNA and protein levels of RACK1 and PKC-ε, accompanied by an increases in ROS production, apoptosis rate, and monolayer permeability. However, silencing RACK1 significantly downregulated the expression of PKC-ε and ROS, reduced cell apoptosis and permeability, and protected barrier function.

Conclusion: RACK1 plays a significant role in the development of early DR and might serve as a potential therapeutic target for DR by regulating RPE apoptosis and barrier function.

Keywords: Adult retinal pigment epithelium cell line-19; Diabetic retinopathy; Protein kinase C-ε; Receptor for activated C kinase 1.